This invention relates to prostaglandin I.sub.2 analogues and uses thereof for circulation ameliorating pharmaceuticals for blood flow amelioration, antithrombotic or antiulcer pharmaceuticals.
Prostaglandin I.sub.2 (hereinafter written as PGI.sub.2) has been known as a natural physiologically active substance and has the stucture shown by the following formula: ##STR2## Its chemical name is (5Z,13E)-(9.alpha.,11.alpha.,15S)-6,9-epoxy-11,15-dihydroxyprost-5,13-dien ic acid. PGI.sub.2 exists within the vascular walls and is the most potent inhibitor of platelet aggregation as well as being a powerful vasodilator [Nature, 263, 663 (1976)].
PGI.sub.2 exhibiting such properties is useful for prophylaxis and therapy of cerebral thrombosis, myocardial infarction and acute stenocardia induced by exasperation of platelet aggregation and further increase of thrombotic tendency, expected to be appicable for prophylaxis and therapy of arteriosclerotic diseases and desired to be developed as the so-called circulation ameliorating or antithrombotic pharmaceuticals.
Also, many prostaglandins containing PGI.sub.2 are known to have gastric mucosa protective effect and blood flow increasing effect within gastric mucosa ['83 Inflammation Seminar "Prostaglandin" Pretext page 50 (sponsored by Society of Inflammation of Japan)], and PGI.sub.2 having such effects can be expected to be applicable for prophylaxis and therapy of gastrointestinal ulcers, typically stomach ulcer.
However, PGI.sub.2 is remarkably unstable and this has been an obstacle against practical application as pharmaceuticals.
In order to overcome such an obstacle, studies have been made about stable analogues in which the oxygen atom between the carbon atoms at the 6- and 9-positions in PGI.sub.2 is replaced with carbon atom. The carbacycline type compounds [Japanese Provisional Patent Publication No. 130543/1979] of the chemical formula (III) as represented by OP-41483 [Japanese Provisional Patent Publication No. 130543/1979] and 9(0)-methano-.DELTA..sup.6 -PGI.sub.1 of the chemical formula (IV) [Japanese Provisional Patent Publication No. 32426/1981] are all chemically stable PGI.sub.2 analogues. Also, 9(0)-methano-.DELTA..sup.6(9.alpha.) -prostaglandin I.sub.1 (isocarbacyclin [Tetrahedron Letters, 24, 3493 (1983)], chemical formula (V)) in which the 5-position double bond in 9(0)-methano-prostacyclin (carbacyclin) is transferred to the 6(9.alpha.) position is also chemically sufficiently stable and has been reported as a PGI.sub.2 analogue having potent physiological properties [Japanese Provisional Patent Publication No. 137445/1984]. ##STR3##